A novel nanovaccine against nicotine addiction smoking is a growing global problem. Chronic use of tobacco is considered a responsible factor for serious diseases such as chronic obstructive pulmonary disease, stroke, chronic lung disease, and cancer. There are more than 60 million smokers in the U.S alone. Despite the urgent need, finding ways to combat the problem has been a constant challenge to the society and the medical field. Current pharmacological therapies have shown very limited success with some serious side-effects, such as depression with suicidal behavior. On the other hand, immunopharmacotherapy or vaccination has emerged as a promising alternative. However, all current vaccines have shown limited efficacy, and thus there is undoubtedly a strong need for improved nicotine vaccines. In this project, building on the tremendous success of a proof-of-concept study (R21DA030083), we propose to synthesize biodegradable nanoparticle based novel nanovaccines against nicotine. Different from all nicotine vaccines that have gone through clinical trials, our nanovaccines will be constructed by assembling lipids around biodegradable nanoparticles, and the carrier proteins with conjugated haptens will be conjugated to the lipids. The innovation of this project involves the use of the biodegradable nanoparticle, immune enhancing lipids, specifically selected carrier proteins, and a molecular adjuvant in the assembly of the nanovaccines. We expect that, through successfully executing the carefully designed experiments, we will be able to identify a leading vaccine candidate that will show unprecedentedly high antibody titers against nicotine and can be advanced into clinical trials. The investigators, with superbly synergizing expertise, are committed to the success of this project. The broad impact of this project resides in the potential of a new and effective vaccine against nicotine, its potential social and economic impact, and a platform technology for producing much needed vaccines against other psychoactive drugs. Our goal is to develop an effective vaccine with controlled size that can elicit strong specific immune response toward nicotine and can be subsequently advanced to clinical trials. To achieve the goal, the following specific aims are proposed: 1) preparation of PLGA nanoparticles, 2) assembly of nanovaccine particles, and 3) evaluation of the immunogenicity and biosafety of the vaccines. With the strong and supportive preliminary results and the collective experiences of the investigators, we strongly believe this project will be extremely successful and eventually lead to the emergence of an effective vaccine against nicotine addiction.